Oncolytic Viruses: converting an old enemy in our ally

Manel Cascalló PhD.CEO, VCN Biosciences

Societat Catalana de Biotecnologia MèdicaMarch 30th, 2017

Our old enemy : viruses

- Viral infection demonstrated to be causal for tumorigenesis in several cancer types (infectious ethiology of cancer)

- Viral infection as causal for many diseases

© American Association for Cancer Research

1911, Peyton Rous (Rockefeller Institute)

Our old enemy : viruses

© American Association for Cancer Research

The other part of the history: an ally?

Liu et al., 2007 Nature Reviews Clinical Oncology

Larson et al. Oncotarget. 2015 Aug 21; 6(24): 19976–19989.)

(28/10/2015)

Oncolytic Viruses: where we are“Infectious Enthusiasm” - BioCentury. 2016 : Feb29th

Oncolytic Viruses: the Identity Crisis

Cancer killers –debulking agents1

Tumor

De novo neo-antigen presentation by effect of viral replication under breakage of

immunotolerance

2 In situ vaccines

Stimulators of innate immune response and heating up

immunologically cold tumors

3 Loco-Regional Adjuvants

Inductors of systemic and long-lasting clinical responses

4 Systemic vaccines

Oncolytic Viruses: the Identity Crisis

Oncolytic Viruses: the Identity Crisis

MASTERKEY-265Trial

ORR: 57%ORR: 56%

(Melanoma)

Reduced toxicity profile compared to a-PD1 / a-CTLA-4 combo treatments described to date

Oncolytic Viruses: AdenovirusWill loco-regional therapy with oncolytic viruses be

sufficient to meet their therapeutic potential?

Oncolytic adenovirus as a well-suited option

Woller N et al. Mol Ther 2015; 1630-1640

Highly cytopathic Easy to be genetically-modifyed Expertise in clinics & industrial manufacturing Highly Inmunogenic Able to broad neoantigen-directed T-cell responses

Neoepitope-specific CD8 T-cell responses(CMT-64 immunocompetent model in mice)

Oncolytic Viruses: Adenovirus

Alemany R. Biomedicines 2014; 2:36-49

Will loco-regional therapy with oncolytic viruses be sufficient to meet their therapeutic potential?

Oncolytic adenovirus as a well-suited option Highly cytopathic Easy to be genetically-modifyed Expertise in clinics & industrial manufacturing Highly Inmunogenic Able to broad neoantigen-directed T-cell responses Able to reach the tumors systemically ?

Oncolytic Adenovirus: VCN-01

HAd5 (wild-type)

Clinical candidateVCN-01

selectivity of replicationin tumour cells

Tumour potency(diffusion)

biodistribution selectivity(tumour targeting)

VCN-01 is and tumor-targeted oncolytic adenovirus armed with hyaluronidase

E2F boxes

-E1A / H&E staining in LIVER after iv injection of 5E10 vp in mice

Rojas et al. Mol Ther 2010; 18(11): 1960-1971 Bayó-Puxan et al. Human Gene Ther 2009; 20:1214-1221

Biodistribution after iv delivery Intratumor Virus spreading

Martínez-Quintanilla et al. Mol Ther 2015; 23(1):108-118

HA staining

Clinical trial of VCN-01 by Intratumor administrationin Pancreatic Cancer

Incidence:

• 45.000/USA• Orphan Indication Obtained by VCN (2012)

Characteristics:

• Highly desmoplastic tumor

• Tumor Matrix as therapeutic target

Current SoC Treatment:• Abraxane/Gemcitabine (1st line)

Problems:• Late detection• Progression free survival 5.5 months; overall

survival 8.5 months

(Extracted from Whatcott et al. (2011) Cancer Discov. Sep;1(4):291-6

Clinical trial of VCN-01 by Intratumor administrationin Pancreatic Cancer

I-13 doses at I-1/dose

+ GE

I-1b3 doses at I-1b/dose

+ GE / Abrx.

US-guided intratumoradministration of VCN-01 (x3)

in combination with nab-paclitaxel / gemcitabine)

Patient Population: Patients with pancreaticadenocarcinoma to be treated with nab-paclitaxel /gemcitabineEndpoints:

a) Primary- Safety &

Tolerability- Definition of RP2D

b) Secondary:- Ability of VCN-01 to

replicate in tumors

Clinical Trial P-VCNA-002 (NCT02045589)

Tumor biopsyElastogram ElastogramElastogram

A Phase I Dose Escalation Study of three Intratumoral VCN-01 Injections with Gemcitabine and Abraxane® in Patients with advanced pancreatic cancer.

Clinical trial of VCN-01 by Intratumor administrationin Pancreatic Cancer

Clinical Trial P-VCNA-002 (NCT02045589)

Positivity for VCN-01 genome in tumor biopsies

Positivity was observed in 85,7% of the tumor biopsies collected at day 21 or 28 post-intratumoraladministration of VCN-01 in the pancreas, strongly suggesting that VCN-01 is replicating in pancreatic tumors

Patient ID Dose Level Cycle 1 Day 1 FNA Date FNA Location vpVCN-01/sample

002-001002 I-1 25-Jun-14 15-Jul-14 Pancreas 1,32E+03002-002001 I-1 06-May-14 27-May-14 Pancreas 1,37E+05002-001004 I-1b 22-Dec-15 23-Feb-16 Pancreas negative002-003001 I-1b 16-Sep-15 27-Oct-15 Pancreas 3,58E+04002-003002 I-1b 30-Dec-15 09-Feb-16 Pancreas 1,69E+03002-002003 I-1b 08-Mar-16 27-May-14 Pancreas 1,49E+03002-002004 I-1b 11-Mar-16 11-Apr-16 Pancreas 8,43E+03002-003003 I-1b 08-Mar-16 18-Apr-16 Pancreas -

Clinical trial of VCN-01 by Systemic administrationin Pancreatic Cancer

Clinical Trial P-VCNA-001 (NCT02045602)A Phase I, multi-center, open-label dose escalation study of intravenous administration of VCN-01 oncolytic adenovirus with or without intravenous gemcitabine and Abraxane® in advanced solid tumors.

Clinical trial of VCN-01 by Systemic administrationin Pancreatic Cancer

Clinical Trial P-VCNA-001 (NCT02045602)VCN-01 levels in blood

Dose administration correlated with VCN-01 levels in blood. Most of the patients administered at the highest dose levels showed secondary viremia peaks and maintained VCN-01 genomes in blood for over 3 weeks after

administration.

Clinical trial of VCN-01 by Systemic administrationin Pancreatic Cancer

Clinical Trial P-VCNA-001 (NCT02045602)

Patient ID

Pre-treatment

AntiAdNabs

Dose Level Cycle 1 Day 1

Biopsy Collection Timepoint

Biopsy Location

vpVCN-01/sample

001-003001 1/10 II-1 19-Aug-15 D8 Pancreas 1,42E+04001-002012 1/40 II-1 16-Sep-15 D8 Liver 1,50E+05001-001013 1/80 II-1 10-Nov-15 D8 Liver 1,95E+04001-003003 1/80 II-1 02-Jun-16 D28 Pancreas negative001-003004 1/80 II-1 08-Jun-16 D28 Pancreas negative001-003005 1/80 II-1 14-Jun-16 D28 Pancreas negative001-001015 1/20 II-2 05-Jan-16 - - -001-002013 1/10 II-2 09-Feb-16 D28 Liver negative001-002014 1/320 II-2 21-Mar-16 D8 Liver 8,24E+02001-003002 1/20 II-2 22-Mar-16 D28 Pancreas negative001-001016 1/320 II-2 06-Sep-16 D28 Pancreas pending001-003006 1/10 II-2 14-Sep-16 - - -

All samples obtained at day 8 after VCN-01 administration were positive for virus presence (both primary or metastaticbiopsies), indicating that VCN-01 reaches the tumor at both II-1 & II-2 doses.

Positivity for VCN-01 genome in tumor biopsies

Clinical trial of VCN-01 by Systemic administrationin Pancreatic Cancer

Clinical Trial P-VCNA-001 (NCT02045602)VCN-01 Antitumor Activity (Part II in combination with GE/Abrx)

a) RECIST v 1.1 criteria (periodically each 8 weeks) (on-going data)

10 patients with evaluable data; 4 of them still on treatment Confirmed Response Rate in 4 out of 10 evaluable patients (40%) 5/9 patients beyond stablished Progression Free Survival, 2 of them beyond Overall Survival 1 Patient showed disease restratification to be surgically amenable (9 months after

treatment initiation) 1 Patient showed Complete Response (15 months after treatment initiation)

Von Hoff et al. Phase III Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine.N.Engl J. Med (2013)

Clinical trial of VCN-01 by Systemic administrationin Pancreatic Cancer

Clinical Trial P-VCNA-001 (NCT02045602)Intratumor staining of Immunological markers

Thank you!!

Dr. Alba de Martino

SCIENTIFIC PARTNERS Dr. Ramon AlemanyDr. Sonia GuedanDr. Alba Rodríguez-GarcíaDr. Luis RojasDr. Mireia MorellDr. Gabriel CapellàDr. Rafael Moreno

Dr. Manel CascallóChief Executive Officermcascallo@vcnbiosciences.com

www.vcnbiosciences.com

CLINICAL PARTNERS Dr. Ramon SalazarDr. Marta GilDr. Berta Laquente

Dr. Manuel HidalgoDr. Rafael Álvarez

Dr. Rocío García-CarboneroDr. Asunción Díaz-SerranoDr. Jaume CatalàDr. Guillermo Chantada

Dr. Ángel Montero CarcabosoGuillem Pascual-Pasto

VCN Biosciences

Dr. Marta GiménezDr. Sara MorgadoDr. Ana Mato Dr. Miriam Bazán-Peregrino

Dr. Gabriel CapellàDr. Ramon Alemany

Dr. Jordi Martínez-QuintanillaFunding:- PANCATHER Project –CDTI PyD- Cure4RB Project – RETOS 2015 (MiNECo)